Unraveling the Molecular Function of Mosaic, a gene mediating immune dysregulation

节目摘要/摘要 免疫调节在耐受和肿瘤监测中起着至关重要的作用。对这些机制的洞察有 来自对IPEX综合征或AIRE患者和动物模型FOXP3突变的研究 APS-1综合征。对这些机制的了解导致了新的治疗方法。陈冯富珍博士的职业生涯 重点是通过研究动物模型和患者，了解免疫调节中的扰动 将生物学转化为临床实践以改善患者护理的目标。 她对免疫失调的兴趣始于她在医学博士培训期间的研究工作。然后，她 获得儿科风湿学和过敏/免疫学委员会认证，以照顾患有以下疾病的患者 她为这个独特的患者队列建立的一家诊所的免疫失调。对这些问题的研究 患者已经发表了几篇论文，其中包括一篇第一作者的论文。 为了继续她的职业发展，她提出了一项为期5年的职业发展计划，将她过渡到 成为一名具有独立研究计划的内科科学家。该计划既培养专业人才，又培养 科学技能以及独立的研究组合。她将得到马克博士的直接指导 安德森和她的顾问委员会，其中包括一群精心策划的知名科学家 以及在T细胞生物学和临床免疫学方面有专长的医生。她提议的课程作业、会议 研讨会将帮助她获得新的技术专长，并提炼专业技能。 她的研究计划集中在解开一种新基因--马赛克背后的分子机制，这种基因 已被确定为犬类多器官系统自身免疫的致病基因。考虑到 马赛克是脊椎动物中一种高度可转换的蛋白质，陈博士培育了几只马赛克小鼠 有初步数据支持T细胞功能的模型。研究方案有三个目标：目标1 明确了马赛克维持外周T细胞动态平衡的机制(S)。目标2定义了 分子途径(S)，通过马赛克改变Th17效应器的功能。目标3决定了 驱动自身免疫的马赛克缺陷。拟议的目标不仅将发展科学技能，还将建立 一个研究组合，以确立她作为一名独立调查员的地位。 她将在加州大学旧金山分校接受培训，这是一个支持内科科学家的理想环境。该部门 儿科大学在培养年轻教师的职业发展方面有着长期的记录。加州大学旧金山分校 免疫学社区包括一大批研究人员，他们在广泛的 研究领域将加速陈博士的个人和专业成长。 总而言之，在完成这个职业发展奖时，陈博士将培养出必要的 有能力发起自己的独立研究计划。这项建议建立在她长期研究的基础上 和对免疫失调的临床兴趣，并将促进她作为一名内科科学家的成功。

PROGRAM SUMMARY/ABSTRACT Immune regulation plays a critical role in tolerance and tumor surveillance. Insight into these mechanisms have arisen from studies on patients and animal models with mutations in FOXP3 for IPEX syndrome or AIRE for APS-1 syndrome. Understanding these mechanisms have led to novel therapies. Dr. Alice Chan’s career focus is to understand perturbations in immune regulation by studying animal models and patients, with the goal of translating the biology into clinical practice to improve patient care. Her interest in immune dysregulation started from her research work during her MD/PhD training. She then became board-certified in both Pediatric Rheumatology and Allergy/Immunology to care for patients with immune dysregulation disorders in a clinic she established for this unique patient cohort. Studies on these patients have led to several publications, including a first author paper. To continue her career development, she has proposed a 5-year career development plan to transition her to become a physician scientist with an independent research program. The plan cultivates both professional and scientific skills as well as an independent research portfolio. She will have direct mentorship by Dr. Mark Anderson and her advisory committee, which includes a carefully curated group of well-recognized scientists and physicians with expertise in T cell biology and clinical immunology. Her proposed coursework, conferences and workshops will help her achieve new technical expertise and refine professional skills. Her research proposal focuses on unraveling the molecular mechanisms behind a novel gene, Mosaic, which has been identified as the causal gene for a multiorgan system autoimmunity in a subset of canines. Given that Mosaic is a highly conversed protein among vertebrates, Dr. Chan has developed several Mosaic mouse models with preliminary data supporting a role in T cell function. The research proposal has 3 aims: Aim 1 defines the mechanism(s) by which Mosaic maintains peripheral T cell homeostasis. Aim 2 defines the molecular pathway(s) through which Mosaic modifies Th17 effector function. Aim 3 determines the ability of defects in Mosaic to drive autoimmunity. The proposed aims will not only develop scientific skills but also build a research portfolio to establish herself as an independent investigator. Her training will be at UCSF which is an ideal environment that supports physician scientists. The Department of Pediatrics has a long track record of fostering the career development of young faculty. The UCSF immunology community includes a broad collection of investigators who are leaders in a wide breadth of research arenas that will accelerate Dr. Chan’s personal and professional growth. In summary at the completion of this career development award, Dr. Chan will have cultivated the necessary skills to launch her own independent research program. This proposal builds on her long-standing research and clinical interest in immune dysregulation and will foster her success as a physician scientist.